*Purpose: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA; CD272) has been implicated in the regulation of autoimmune and may potentially play an important role in alloimmune responses. We investigated the effects of agonistic anti-BTLA monoclonal antibody (6B2) on alloimmune responses in a murine model of cardiac allograft transplantation.

*Methods: CBA mice (H2^k) underwent transplantation of C57BL/6 (H2^b) hearts and received four doses of 6B2 on day 0, 3, 6 and 9. Adoptive transfer study, flow cytometry study, and immunohistochemical (IHC) study were performed .

*Results: Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 7 days). CBA recipients exposed with four doses of 6B2 significantly prolonged allograft survival (MST, >100 days). Secondary CBA recipients given whole splenocytes from primary 6B2-exposed CBA recipients with beating B6 cardiac allografts 30 days after transplantation had prolonged B6 allograft survival (MST, >100 days). Histological studies showed that cardiac allografts from 6B2-exposed recipients had sparse cell infiltration and only slight myocardial damage and IHC showed more CD4⁺Foxp3⁺ cells in myocardiumon on day 30 after transplantation. Additionally, flow cytometry studies show an increased CD4⁺CD25⁺Foxp3⁺ cell population in splenocytes from 6B2-exposed recipients and suppressed donor specific antibody (DSA) on day 30 and 100 after transplantation.

*Conclusions: 6B2 could induce the prolongation of fully MHC-mismatched cardiac allograft through an increase of CD4⁺CD25⁺Foxp3⁺ regulatory T cells and consequently the suppression of DSA.

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